Elsevier

The Lancet

Volume 376, Issue 9742, 28 August–3 September 2010, Pages 687-697
The Lancet

Articles
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial

https://doi.org/10.1016/S0140-6736(10)61121-XGet rights and content

Summary

Background

Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer.

Methods

ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404.

Findings

594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18·6 months (IQR 11–25) in the trastuzumab plus chemotherapy group and 17·1 months (9–25) in the chemotherapy alone group. Median overall survival was 13·8 months (95% CI 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11·1 months (10–13) in those assigned to chemotherapy alone (hazard ratio 0·74; 95% CI 0·60–0·91; p=0·0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups.

Interpretation

Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer.

Funding

F Hoffmann-La Roche.

Introduction

Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related deaths worldwide.1, 2 Most patients present with inoperable advanced or metastatic disease requiring palliative treatment, although early detection is more common in Asia than in other regions. In the UK MAGIC study,3 5-year survival was 36% in patients with operable disease who were assigned to perioperative chemotherapy. However, 5-year survival for advanced or metastatic gastric cancer is around 5–20%, with median overall survival being less than 1 year.2, 4, 5 A meta-analysis of phase 2 and 3 randomised gastric cancer trials has shown that combination chemotherapy results in substantially improved overall survival compared with single-agent chemotherapy or best supportive care.6 Typically, a fluoropyrimidine and a platinum compound form the backbone of chemotherapy for patients with advanced gastric cancer. There is currently no single well established standard of care, but fluoropyrimidine-based and platinum-based combinations with or without a third drug (usually docetaxel or epirubicin) are the most widely used combinations in Europe and the USA. The oral fluoropyrimidine capecitabine was shown to be non-inferior to fluorouracil in terms of progression-free survival and overall survival in clinical trials.7, 8

Despite the recently reported benefits of combination therapies, the prognosis of advanced gastric or gastro-oesophageal cancer remains poor, and new treatments showing acceptable toxicity profiles are urgently needed. One well established target is human epidermal growth factor receptor 2 (HER2; also known as ERBB2), a member of a family of receptors associated with tumour cell proliferation, apoptosis, adhesion, migration, and differentiation.9 There is growing evidence that HER2 is an important biomarker and key driver of tumorigenesis in gastric cancer, with studies showing amplification or overexpression in 7–34% of tumours.9, 10, 11 Although reports are conflicting, some studies have suggested that HER2-positive status in gastric cancer is associated with poor outcomes and aggressive disease.9, 11

Trastuzumab, a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity, inhibits HER2-mediated signalling, and prevents cleavage of the extracellular domain of HER2.12 In HER2-positive breast cancer, trastuzumab has shown a survival advantage in early and metastatic disease and is now the standard of care.13, 14, 15 In patients with metastatic breast cancer, high levels of HER2-protein expression and amplification predict for better outcomes with trastuzumab.14 However, this relation is less clear in patients with early breast cancer16 and has not been established in other tumour types with HER2 overexpression. In preclinical models of gastric cancer, trastuzumab showed at least additive antitumour effects when combined with capecitabine or cisplatin, or both.17 In view of the high unmet medical need in gastric cancer, a HER2 positivity rate similar to breast cancer,18, 19, 20 and the good tolerability profile of trastuzumab in patients with breast cancer,13, 15 investigation of trastuzumab in patients with gastric cancer was warranted.

The objective of the Trastuzumab for Gastric Cancer (ToGA) study was to assess the clinical efficacy and safety of trastuzumab added to chemotherapy for first-line treatment of advanced gastric or gastro-oesophageal junction cancers with overexpression of HER2.

Section snippets

Study design and participants

ToGA was a randomised, open-label, multicentre, international, phase 3, randomised controlled trial undertaken in 24 centres in Asia, Central and South America, and Europe. Men or women older than 18 years of age were eligible for inclusion if they had histologically confirmed inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction; Eastern Cooperative Oncology Group (ECOG) performance status 0–2; adequate organ function; and measurable

Results

Figure 1 shows the trial profile. Between September, 2005, and December, 2008, 594 patients were randomly assigned to study treatment at 122 centres in 24 countries. 584 randomised patients who received study treatment at least once were included in the analysis.

Table 2 shows demographics and baseline disease characteristics of patients included in the analysis. Most patients received a chemotherapy regimen that included capecitabine (88%). High expression of HER2 protein (ie,

Discussion

In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Furthermore, an exploratory, post-hoc analysis showed that trastuzumab plus chemotherapy substantially improved overall survival in patients with high expression of HER2 protein (immunohistochemistry 2+ and FISH positive or immunohistochemistry 3+) compared with patients with low expression of HER2 protein

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